CREBH Couples Circadian Clock With Hepatic Lipid Metabolism

Diabetes. 2016 Nov;65(11):3369-3383. doi: 10.2337/db16-0298. Epub 2016 Aug 9.


The circadian clock orchestrates diverse physiological processes critical for health and disease. CREB, hepatocyte specific (CREBH) is a liver-enriched, endoplasmic reticulum (ER)-tethered transcription factor known to regulate the hepatic acute phase response and energy homeostasis under stress conditions. We demonstrate that CREBH is regulated by the circadian clock and functions as a circadian regulator of hepatic lipid metabolism. Proteolytic activation of CREBH in the liver exhibits typical circadian rhythmicity controlled by the core clock oscillator BMAL1 and AKT/glycogen synthase kinase 3β (GSK3β) signaling pathway. GSK3β-mediated phosphorylation of CREBH modulates the association between CREBH and the coat protein complex II transport vesicle and thus controls the ER-to-Golgi transport and subsequent proteolytic cleavage of CREBH in a circadian manner. Functionally, CREBH regulates circadian expression of the key genes involved in triglyceride (TG) and fatty acid (FA) metabolism and is required to maintain circadian amplitudes of blood TG and FA in mice. During the circadian cycle, CREBH rhythmically regulates and interacts with the hepatic nuclear receptors peroxisome proliferator-activated receptor α and liver X receptor α as well as with the circadian oscillation activator DBP and the repressor E4BP4 to modulate CREBH transcriptional activities. In conclusion, these studies reveal that CREBH functions as a circadian-regulated liver transcriptional regulator that integrates energy metabolism with circadian rhythm.

MeSH terms

  • ARNTL Transcription Factors / genetics
  • ARNTL Transcription Factors / metabolism
  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Chromatin Immunoprecipitation
  • Circadian Clocks / genetics
  • Circadian Clocks / physiology*
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Fatty Acids / metabolism
  • Glycogen Synthase Kinases / genetics
  • Glycogen Synthase Kinases / metabolism
  • Hepatocytes / metabolism
  • Lipid Metabolism / genetics
  • Lipid Metabolism / physiology
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mutagenesis, Site-Directed
  • Protein Binding
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Triglycerides / metabolism


  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Basic-Leucine Zipper Transcription Factors
  • Creb3l3 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Fatty Acids
  • Nfil3 protein, mouse
  • Triglycerides
  • Glycogen Synthase Kinases